rs150096625

Variant names:

• chr12-21910277-C-T
• rs150096625
• NM_020297.4:c.1200G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_020297.4(ABCC9):​c.1200G>A​(p.Thr400Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000555 in 1,602,844 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00036 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ABCC9 NM_020297.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.875
• Publications: 0 publications found

Genes affected

ABCC9 (HGNC:60): (ATP binding cassette subfamily C member 9) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein is thought to form ATP-sensitive potassium channels in cardiac, skeletal, and vascular and non-vascular smooth muscle. Protein structure suggests a role as the drug-binding channel-modulating subunit of the extra-pancreatic ATP-sensitive potassium channels. Mutations in this gene are associated with cardiomyopathy dilated type 1O. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2011]

ABCC9 Gene-Disease associations (from GenCC):

• hypertrichotic osteochondrodysplasia Cantu type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• dilated cardiomyopathy 1O

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• intellectual disability and myopathy syndrome

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• acromegaloid facial appearance syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrichosis-acromegaloid facial appearance syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation, familial, 12

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 12-21910277-C-T is Benign according to our data. Variant chr12-21910277-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.875 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000363 (53/145852) while in subpopulation AFR AF = 0.00135 (53/39230). AF 95% confidence interval is 0.00106. There are 1 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020297.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC9	NM_020297.4	MANE Select	c.1200G>A	p.Thr400Thr	synonymous	Exon 10 of 40	NP_064693.2	O60706-2
	ABCC9	NM_001377273.1		c.1200G>A	p.Thr400Thr	synonymous	Exon 11 of 41	NP_001364202.1	O60706-2
	ABCC9	NM_005691.4		c.1200G>A	p.Thr400Thr	synonymous	Exon 10 of 41	NP_005682.2	O60706-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC9	ENST00000261200.9	TSL:5 MANE Select	c.1200G>A	p.Thr400Thr	synonymous	Exon 10 of 40	ENSP00000261200.4	O60706-2
	ABCC9	ENST00000261201.10	TSL:5	c.1200G>A	p.Thr400Thr	synonymous	Exon 10 of 41	ENSP00000261201.4	O60706-1
	ABCC9	ENST00000879186.1		c.1200G>A	p.Thr400Thr	synonymous	Exon 9 of 39	ENSP00000549245.1

Frequencies

GnomAD3 genomes AF: 0.000336 AC: 49 AN: 145768 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000567 AC: 14 AN: 247066 AF XY: 0.0000449

Gnomad AFR exome AF: 0.000805

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000247 AC: 36 AN: 1456992 Hom.: 0 Cov.: 31 AF XY: 0.0000235 AC XY: 17 AN XY: 724738

African (AFR) AF: 0.000662 AC: 22 AN: 33254

American (AMR) AF: 0.0000225 AC: 1 AN: 44400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1109764

Other (OTH) AF: 0.0000664 AC: 4 AN: 60198

GnomAD4 genome AF: 0.000363 AC: 53 AN: 145852 Hom.: 1 Cov.: 31 AF XY: 0.000383 AC XY: 27 AN XY: 70408

African (AFR) AF: 0.00135 AC: 53 AN: 39230

American (AMR) AF: 0.00 AC: 0 AN: 14492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 4998

South Asian (SAS) AF: 0.00 AC: 0 AN: 4672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66974

Other (OTH) AF: 0.00 AC: 0 AN: 2030

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000340

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	ABCC9-related disorder (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1O (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	5.7
DANN	Benign	0.70
PhyloP100		-0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs150096625; hg19: chr12-22063211; COSMIC: COSV53975068;